N,n{40 -bis-{8 (1-amido 2,2,2 trichloro)-ethyl{9 -piperazine

ABSTRACT

Biocidal compounds of the formula   WHEREIN R is hydrogen or lower alkyl which may have one or more halogen atoms attached thereto, R1 is hydrogen, lower alkyl or phenyl, and R2, R3 and R4 are each hydrogen or lower alkyl.

United States Patent 0st et al.

54] N,N-BlS-[(1-AMIDO 2,2,2

TRlCHLORO)-ETHYL]-PIPERAZINE [72] Inventors: Walter 0st, Klaus Thomas,Dietrich Jerchel, all of Ingelheim/Rhine; Karl-Richard Appel, Biberach/Risscgg, all of Germany [73l Assignee: C. H. Boehringer soh, lngelheim/Rhine, Germany [22] Filed: Nov. 4, 1970 [21] Appl. No.: 87,015

Related US. Application Data [63] Continuation-impart of Ser. No.793,187, Jan.

22, 1969, Pat. No. 3,595,916.

[30] Foreign Application Priority Data 51 Oct. 3, 1972 PrimaryExaminer-Donald G. Daus Attorney-Hammond & Littell [57] ABSTRACTBiocidal compounds of the formula wherein R is hydrogen or lower alkylwhich may have one or more halogen atoms attached thereto,

R is hydrogen, lower alkyl or phenyl, and R R, and R are each hydrogenor lower alkyl.

4 Claims, No Drawings v wherein R has the same meanings as in Formula 1and X N,N'-BIS-[(l-AMIDO 2,2,2 TRICHLORO)-ETHYL]- PIPERAZINE This is acontinuation-in-part of copending application, Ser. No. 793,187, filedJan. 22, 1969, now U.S. Pat. No. 3,595,916 issued July 27, 1971.

This invention relates to novel piperazine compounds, as well as to amethod of preparing the same.

More particularly, the present invention relates to a novel class ofpiperazine compounds of the formula wherein R is hydrogen or straight orbranched lower alkyl which may have one or more halogen substituentsattached thereto,

R is hydrogen, lower alkyl or phenyl, and

R R and R are each hydrogen or lower alkyl.

A compound of the formula 1 may be prepared by reacting a compound ofthe formula X (II) wherein R R R and R have the same meanings as inFormula I, pursuant to the following reaction formula (II) (III) Thereaction is preferably carried out in the presence of an inert organicsolvent, such as tetrahydrofuran, dioxane, toluene, acetone or achlorinated hydrocarbon, at a temperature between about C. and +100 C.,preferably between +20 C. and +40 C.

When X in Formula 11 is chlorine or bromine it is advantageous to addtov the reaction mixture an equivalent amount of a tertiary amine, suchas triethylamine. In those instances it is assumed that a reactiveintermediate of the formula RCO--N= CH--CC1;, is formed, which thenreacts further to undergo an additional reaction with the piperazine 111and forms a compound of the formula 1.

The end products of the Formula 1 thus obtained are weak bases; they arecolorless crystalline solids which are sparsely soluble in water.However, all of the bases are relatively easily soluble indimethylsulfoxide,

invention and will enable others skilled in the art to understand itmore completely. It should be understood, however, that the invention isnot limited solely to the particular examples given below.

EXAMPLE 1 Preparation of N,N'-bis-[( 'l -acetamido-2,2,2-trichloro)-ethyl]-piperazine While stirring, a solution of 3.44 gm 0.04mol) of piperazine and 8.2 gm (0.081 mol) of triethylamine in 60 cc ofperoxide-free tetrahydrofuran was added dropwise to a solution of 18.0gm (0.08 mol) of N- (1,2,2,2-tetrachloro-ethy1)-acetamide in 50 cc ofperoxide-free tetrahydrofuran. Thereafter, the reaction mixture wasallowed to stand for one hour at room temperature, then vacuum-filtered,the filter cake of triethylamine hydrochloride was washed withtetrahydrofuran, and the filtrate was evaporated in vacuo. Thesemi-solid residue was digested with ether, and the crystalline productformed thereby was separated by vacuum filtration and washed with ether,yielding 15.1 gm (8] percent of theory) of a colorless substance whichwas recrystallized from isopropanol. The product was identified to beN,N'-bis-[( 1- acetamido-Z,2,2-trichloro)-ethyl]-piperazine,decomposition point about C. (depending upon the rate of heating), ofthe formula 0 aC-ii-NH-CH-CCI:

Analysis:

Calculated: C 31.13%;11 3.92%; N 12.10% Found: C 31.07%; H 4.13%; N11.94%

EXAMPLE 2 Using a procedure analogous to that described in Example 1,N,N'-bis-[( 1-dichloroacetamido-2,2 ,2- trichloro)-ethy1]-piperazine,decomposition point about 180 C., of the formula was prepared fromN-(1,2,2,2-tetrach1oro-ethyl)- dichloroacetamide and piperazine. Theyield was 94 percent of theory.

Analysis:

Calculated: C-23.99%; 1-12.35%; Cl59.0l%;

N-9.33% Found: C-24.16%; H2.33%; Cl58.5%; N-

EXAMPLE 3 Using a procedure analogous to that described in Exnmplc lN,N'-bis-[( l-trich1oroacetamido-2,2,2- trichloro)-cthyll-piperazine,decomposition point about 180 C., of the formula i ClaC-C-NH-CH-C Ch wasprepared from N-( 1,2,2,2-tetrach1oroethy1)- trichloroacetamide andpiperazine. The yield was 45 percent of theory.

Analysis:

Calculated: C 21.52%; H 1.81%; N 8.36% Found: C 21.40%; H 1.95%; N 8.31%

EXAMPLE 4 Using a procedure analogous to that described in ExampleN,N'-bis-[( 1-formamido-2,2,2-trichloro)- ethyl]- Z-methyl-piperazine,decomposition point about 167 C., of the formula was prepared fromN-(1,2,2,2-tetrachloro-ethy1)-formamide and 2methyl-piperazine. Theglassyamorphous residue remaining after evaporation of thetetrahydrofuran solution was dissolved in methylene chloride whilegently heating, and after a few minutes of standing the reaction productcrystallized out of the solution in the form of colorless crystals. Theyield was 79 percent of theory.

EXAMPLE 5 Using a procedure analogous to that described in Example 1,N,N'-bis-[( l-trimethy1acetamido-2,2,2- trichloro)-ethyl]-piperazine,decomposition point ample about 200 C., of the formula was prepared fromN-( l,2,2,2-tetrachloro-ethy1)-piva1- ic acid amide and piperazine. Theproduct partially precipitated from the tetrahydrofuran solutiontogether with the triethylamine hydrochloride; a second fraction wasobtained by evaporating the mother liquor in vacuo. The total yield waspercent of theory.

Analysis:

Calculated: C 39.51%; H 5.53%; N 10.24% Found: C 39.79%; H 5.72%; N10.26%

EXAMPLE 6 Using a procedure analogous to that described in Ex- 1,N,N-bis-[( l-chloroacetamido-2,2,2- trichloro)-ethy1])-piperazine,decomposition point about 173 C., of the formula was prepared from N-( l,2,2,2-tetrachloroethyl)- chloroacetamide and piperazine. The yield was86 percent of theory.

Analysis:

Calculated: C 27.08%; H 3.03%; N 10.53% Found: C 27.12%; H 2.86%; N10.20%

EXAMPLE 7 18.7 gm (86 percent of theory). The product wasrecrystallizable from dioxane.

Analysis:

Calculated: C 27.61%; H 3.24%; N 12.88- Found: C 27.90%; H 3.38%; N12.68%

EXAMPLE 8 N,N'-Bis-[( l-formamido-2,2,2-trichloro )-ethy1]- piperazine21.1 gm (0.1 mol) of powdered N-(l,2,2,2- tetrachloro-ethyl)-formamidewere suspended in 50 cc of water and, while stirring, a mixture of 4.3gm (0.05 mol) of piperazine, 10.1 gm 0.1 mol) of triethylamine and 50 ccof water was added dropwise to the suspension at 20 25 C. Thereafter,the reaction mixture was stirred for 30 minutes more at roomtemperature, the aqueous phase was decanted, and the tacky crystallineresidue was digested with 30 cc of methanol, vacuum filtered, and washedwith methanol. 50 percent of theory of N,N'-bis-[(1-formamido-2,2,2-trichloro)- ethyl]-piperazine was obtained.

EXAMPLE 9 N,N'-Bis-[( l-formamido-2,2,2-trichloro )-ethyl]- piperazine5.3 gm (0.05 mol) of sodium carbonate were added to a solution of 21.1gm 0.1 mol) of N-(l,2,2,2- tetrachloroethyl)-formamide in 50 cc ofacetone, and then, while stirring, a solution of 4.3 gm (0.05 mol) ofpiperazine in 50 cc of acetone was added dropwise. Thereafter, thereaction mixture was stirred for thirty minutes more, the acetone wasdistilled off in vacuo, and the residue was washed first with water andthen with cold methanol and finally dried. The yield was 77 percent oftheory of N,N'-bis-[(1-formamido-2,2,2- trichloro)-ethyl]-piperazine.

EXAMPLE 10 Using a procedure analogous to that described in Example 1,N,N'-bis-[( 1-propionamido-2,2,2-trichloro)- ethyl]-piperazine,decomposition point l84-185 C., of the formula was prepared from N-[(l,2,2,2-trichloro)-ethyl]- propionamide and piperazine. The yield was 45percent of theory.

EXAMPLE 1 1 Using a procedure analogous to that described in ExampleN,N'-bis-[( 1 -propionamido-2,2,2-trichloro)-ethylI-Z-methyl-piperazine, decomposition point -l67 C., of the formulawas prepared from N-[(l,2,2,2-tetrachloro)-ethyl] propionamide and2-methyl-piperazine. The yield was 66 percent of theory.

EXAMPLE 12 Using a procedure analogous to that described in Example lN,N'-bis-[( l-fluoroacetamido-2,2 ,2- trichloro-ethyll-piperazine,decomposition point 163-l 68 C., of the formula was prepared fromN-[(1,2,2,2-tetrachloro)-ethyl]- fluoroacetamide and piperazine. Theyield was 64 percent of theory.

EXAMPLE 13 Using a procedure analogous to that described in Example 1N,N'-bis-[( 1-fluorocentamido-2,2,2-trichloro)-ethy1I-Z-methyl-piperazine, decomposition point 138-142 C.,of the formula was prepared from N-[(1,2,2,2-tetrachloro)-ethyl]-fluoroacetamide and Z-methyI-piperazine. The yield was 29 percent oftheory.

EXAMPLE 14 Using a procedure analogous to that described in Example 1,N,N-bis-[( 1-trichloroacetamido-2,2,2-trichloro)-ethyl]-2methyl-piperazine, decomposition point l30-135 C., ofthe formula was prepared from N-[( l ,2,2,2-tetrachloro)-ethyl]-for- Qmamide and a stereoisomeric mixture of 2,3,5,6-

tetramethyl-piperazine. The yield was 45 percent of N CH: I EXAMPLE 18Clc C NH HC Using a procedure analogous to that described in Example 1,N,N-bis-[( l-formamido-2,2,2-trichloro)- Iethyl]-2,3-trans-dimethyl-piperazine, decomposition was prepared fromN-[( l,2,2,2-tetrachloro)-ethyl]- Point 0 c" ofthe formulatrichloroacetamide and Z-methyl-piperazine. The yield was 50% of theory.E

EXAMPLE 15 H- y Usmg a procedure analogous to that described in Examplel, N,N-bis-[( l-trifluoroacetamido-2,2,2- I OHtrichloro)-ethyl]-piperazine, decomposition point 155-1 58 0., of theformula 20 0 F,c-ll-NH-cH 0c13 r i l; was prepared from N-[(l,2,2,2-tetrachloro)-ethyl]-formamide and trans-2,3-dimethyl-piperazine.The yield j was 17 percent of theory.

EXAMPLE 19 Using a procedure analogous to that described in Example l,N,N'-bis-[( l-formamido-2,2,2-trichloro)- was prepared from N-[(l,2,2,2-tetrachloro)-ethyl]- ethyl]-trans-2-methyl-3-ethyl-piperazine,decompositrifluoroacetamide and piperazine. The yield was 76 P Oftheformula percent of theory.

0 EXAMPLE l6 H-(i-NH-(fH-C 01, Using a procedure analogous to thatdescribed in Ex- CH3 ample l, N,N-bis-[( l-formamido-2,2,2-trichloro)-ethyll- 2,5-dimethyl-piperazine, decomposition point i 184 C., of theformula O HCNHCH-C Ch N was prepared from N-[( l,2,2,2-tetrachloro)-ethyl]-formamide and trans-2-methyl-3-ethyl-piperazine. The HaC- Nyield was 15 percent of theory.

H(IJ'NH(!IHC c1, EXAMPLE 20 6 Using a procedure analogous to thatdescribed in Exa. ample 1, N,N'-bis-[( l-formamido-2,2,2-trichloro)- wasprepared from N-[( l,2,2,2-tetrachloro)-ethyl]-fory l Y 'P Pdecomposition mamide and a mixture of cisand trans-isomers of 2,5- P C,was P P m dimethyl-piperazine. The yield was 28 percent of p y andc1S-2,3-dlmethy]' theory piperazine. The yield was 36 percent of theory.

EXAMPLE 17 EXAMPLE 2] Using a procedure analogous to that described inEx- Using a Procedure analogous to that described in ample l,N,N'-bis-[( l-formamido-2,2,2-trichloro)- ample 1, f- -ll Z 9ethyl]-2,3,5,6-tetramethyl-piperazine, decomposition y l- 'p y 'pdecomposlllon P point 180 C., of the formula Ofthe la 13 N H H30 x0113Cu 5 HzC- N C 3 N was prepared from N-[(l,2,2,2-tetrachloro)-ethyll-formamide and Z-phenyl-piperazine. The yieldwas 16 percent of theory.

EXAMPLE 22 Using a procedure analogous to that described in Example l,N,N'-bis-[( l-formarnido-2,2,2-trichlor)- ethyl]-2-ethyl-piperazine,decomposition point l64-l 66 C., of the formula 0 H-(i-NH-(fEL-C on NICiHi N HC--NH-(]J 11-0 013 was prepared from N-[(l,2,2,2-tetrachloro)-ethyl]-formamide and 2-ethyl-piperazine. The yieldwas 40 percent of theory.

EXAMPLE 23 Using a procedure analogous to that described in Example l,N,N'-bis-[( l-formamido-2,2,2-trichloroethyl]-2,3,S-trimethyl-piperazine, decomposition point 168 C., of theformula 0 H-i-NH-CH-C Cl:

was prepared from N-[( l,2,2,2-tetrachloro)-ethyl]-formamide and astereoisomeric mixture of 2,3,5- trimethyl-piperazine. The yield was 12percent of theory.

EXAMPLE 24 Using a procedure analogous to that described Exwas preparedfrom N-[( l,2,2,2-tetrachloro )-ethyl]-formamide and2-n-propyl-piperazine. The yield was percent of theory.

EXAMPLE 25 Using a procedure analogous to that described in Ex- 10 amplel, N,N'bis-[( l-formamido-2,2,2 trichloro)-ethyl]-2,6-dimethyl-piperazine, decomposition point 17 l-l 72 C., ofthe'formula H-C-NH- H-C Ch was prepared from N-[(l,2,2,2-tetrachlor0)-ethyl]-formamide and 2,6-dimethyl-piperazine. Theyield was 1 1 percent of theory.

EXAMPLE 26 N,N'-Bis-[( l-formamido-2,2,2-trichloro)-ethyl]- piperazine.

A mixture consisting of 2.1 gm (0.025 mol) of piperazine, 5.1 gm 0.05mol) of triethylamine, 6.8 gm (0.05 mol) ofl-formamido-2,2,2-trichloro)-ethoxy]- benzene and 50 cc of absolutetetrahydrofuran was allowed to stand for 14 hours at room temperature,and thereafter was refluxed for 2 hours. Subsequently,- the reactionsolution was filtered, the filtrate was evaporated in vacuo, and theviscous brown residue, which had an odor of phenol, was digested with 15cc of methanol. After several hours of standing, about 10 percent oftheory of N,N'-bis-[( l-formamido-2,2,2- trichloro)-ethyl]-piperazinehad crystallized out.

The starting compound, l-formamido2,2,2- trichloro)rethoxy]-benzene,m.p. 93-94 C., was obtained with a yield of 83 percent of theory from N-l,2,2,2-tetrachloro)-ethyl]-formamide and phenol in the presence oftriethylamine.

EXAMPLE 27 N,N'-Bis-[( l-formamido-2,2,2-trichloro)-ethyl]- piperazine.

1.2 gm (0.014 mol) of piperazine and 7.1 gm (0.028 mol) ofl-formamido-l-(methylsulf0nyl)-2,2,2- trichloro1-ethane were dissolvedin 50 cc of absolute tetrahydrofuran, 2.9 gm (0.028 mol) oftriethylamine were added to the solution, and the mixture was allowed tostand for several hours at room temperature. Thereafter, the reactionsolution was diluted with water, and the precipitate formed thereby wascollected by vacuum filtration and washed first with water and then withmethanol. 96 percent of theory of N,N'- bis-[l-formamido-2,2,2-trichloro)-ethyl]-piperazine were obtained.

The starting compound,l-formamido-l-(methylsulfonyl)-2,2,2-trichloro1-ethane, m.p. l32-l33 C.,was prepared in the following manner: N-[( 1 ,2,2,2-tetrachloro)-ethyl]-formamide was first reacted with methylmercaptan inthe presence of triethylamine, yielding 82 percent of theory of(l-formamido-lmethylmercaptO-Z,2,2-trichloro)-ethane, m.p. l2 2-l2 3 C.,which was subsequently oxidized with hydrogen peroxide in acetic acid at20 C. The yield was 66 percent of theory.

The compounds according to the present invention,

that is, those embraced by Formula 1 above, have useful properties. Moreparticularly, the compounds of the invention are highly effectivefungicides with very low phytotoxicity; thus they may be effectivelyused for prophylactic as well as curative treatment of plants againstphytopathogenic fungi. For instance, complete prevention againstinfestation is achieved in the case of a number of true mildew fungi,such as Erysiphe graminis and Erysiphe polygoni. Furthermore, thecompounds according to the invention are effective in combatting rustfungi, such as Uromycesfabae and Puccinia arenariae; causes of wiltingdiseases, such as Verticillium alboatrum; causes of plant scabs, such asVenturia inaequalis; mold fungi, such as Aspergillus niger; and variousother harmful fungi, such as Fusaria and Ophiobuli.

Particularly noteworthy is a good systemic effect of the novelcompounds.

The compounds according to the present invention are also useful asanthelmintics and enhance the germination of seeds, such as pea andcotton seeds.

The compounds of the Formula I also exhibit very low toxicity towardwarm-blooded animals.

For prophylactic or curative treatment of plants against fungusinfestation, the compounds according to the present invention areincorporated as active ingredients into customary fungicidalcompositions, i.e., compositions consisting essentially of a liquid orcomminuted solid inert carrier and an effective fungicidal amount of theactive ingredient, such as solutions, emulsion concentrates, suspendableor wettable powders, dusting powders, granulates and sprays. The activeingredient content of these compositions is about 0.5 to 85 percent byweight, preferably 0.5 to 50 percent by weight.

For instance, an emulsion concentrate contains about 0.5 to 20 percentby weight, preferably 5 to percent by weight, of a compound of theFormula 1. Suitable solvents for the preparation of emulsionconcentrates comprising a compound of the invention as an activeingredient are, for example, mixtures of dimethylformamide orN-methylpyrrolidone with alcohols or glycols. Suitable emulsifiers andwetting agents which may be used for the preparation of such emulsionconcentrates are ionic or non-ionic compounds, such as nonylphenolpolyglycol ether, or mixtures of non-ionic and ionic, preferablyanionic, compounds as well as ampholytes. The emulsifier content of theemulsion concentrate is about 0.5 to 45 percent by weight, preferably 5to 40 percent by weight.

The active ingredient content of a wettable powder is about 0.5 to 80percent by weight, preferably to 60 percent by weight. Suitableemulsifiers and wetting agents which may be used for the preparation ofwettable powders are non-ionic or ionic compounds of the type describedin the preceding paragraph; the total amount of emulsifier and wettingagent in such wettable powders is about 0.5 to percent by weight,preferably 2 to 25 percent by weight. Suitable powdery inert carriersare, for example, bentonite, kaolin and colloidal silicic acid.

The fungicidal compositions comprising a compound of the presentinvention as an active ingredient are, if necessary, diluted with waterto an active ingredient concentration of 0.5 to 0.00001 percent prior totheir EXAMPLE 28 Dusting Powder N,N'-Bis-[( l-formamido-2,2,2-

trichloro)-ethyl]-piperazine 1% Talcum 98% Methylcellulose 1% Thecomponents were admixed with each other, and the mixture was milleduntil homogeneous. The resulting powder was an effective fungicidalcomposition, especially against mildew and the like.

EXAMPLE 29 wettable Powder trichloro)-ethy1l-2-methylpiperazine 25%Kaolin 55% Colloidal silicic acid 10% Lignin sulfonate (dipersing agent)9% Sodium tetrapropylene benzene sulfonate (wetting agent) 1% Thecomponents were admixed, the mixture was milled until homogeneous, andprior to use the powder was suspended in an amount of water such thatthe active ingredient concentration in the aqueous suspension was from0.00001 to 0.5 percent by weight. The suspension was an effectivefungicidal spray, especially against mildew and the like.

EXAMPLE 30 Emulsion Concentrate N,N'-Bis-[( l-acetamido-2,2,2-

trichloro)-ethy1]-piperazine 10% Sodium tetrapropylene benzene sulfonate(anionic emulsifier) 5% Nonylphenol polyglycol ether (non-ionicemulsifier) 20% Propyleneglycol 32.5% N-Methylpyrrolidone 32.5%

The components were uniformly admixed with each other, and prior to usethe resulting concentrate was diluted with water to the desired activeingredient content between 0.00001 and 0.5 percent by weight. Theresulting aqueous emulsion was an effective fungicidal spray, especiallyagainst mildew and the like.

EXAMPLE 31 Aerosol Spray N,N'-Bis-[( l-trichloroacetamido-2,2,2-trichloro)-ethy1]- piperazine 0.05% Sesame oil 0.10%N-Methylpyrrolidone 10.00% Propellant gas 89.85%

The components were admixed in customary fashion, and the mixture wascharged into aerosol containers provided with a spray valve. Theresulting aerosol was an effective fungicidal spray, especially againstmildew Wettahlc powder N,N'-Bis-[( l-trimcthylamido-2,2,2-trichloro)-cthyl]- piperazinc 85% Calcium lignin sulfonate 8%Colloidal silicic acid Diisobutyl naphthalene sodium sulfonatc 2% Thecomponents were admixed, the mixture was milled until homogeneous, andprior to use the powder was suspended in an amount of water such thatthe active ingredient concentration in the aqueous suspension was from0.00001 to 0.5 percent by weight. The suspension was an effectivefungicidal spray, especially against mildew and the like.

Analogous results were obtained when any one of the other compoundsembraced by Formula I was substituted for the particular piperazinecompounds in Examples 28 through 32. Likewise, the amounts and nature ofthe inert ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. Acompound of the formula ll R-C-NH-CH-CCI:

phelnyl, R215 ydrogen, methyl or ethyl, and

R and R are each hydrogen or methyl.

3. The compound according to claim 1 which is N,N-bis-[(l-formamido-2,2,2-trichloro )-ethyl] -2- methyl-piperazine.

4. The compound according to claim 1 which is N,N'-bis-[(l-formamido-2,2,2-trichloro)-ethyl]- piperazine.

2. A compound according to claim 1, wherein R is hydrogen, alkyl of oneto four carbon atoms, chloromethyl, dichloromethyl, trichloromethyl,fluoromethyl or trifluoromethyl, R1 is hydrogen, alkyl of one to threecarbon atoms or phenyl, R2 is hydrogen, methyl or ethyl, and R3 and R4are each hydrogen or methyl.
 3. The compound according to claim 1 whichis N,N''-bis-((1-formamido-2,2,2-trichloro)-ethyl)-2-methyl-piperazine.4. The compound according to claim 1 which isN,N''-bis-((1-formamido-2,2,2-trichloro)-ethyl)-piperazine.